Can SARS-CoV-2 Virus Use Multiple Receptors to Enter Host Cells?

Abstract

The occurrence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVD-19), represents a catastrophic threat to global health. Protruding from the viral surface is a densely glycosylated spike (S) protein, which engages angiotensin-converting enzyme 2 (ACE2) to mediate host cell entry. However, studies have reported viral susceptibility in intra- and extrapulmonary immune and non-immune cells lacking ACE2, suggesting that the S protein may exploit additional receptors for infection. Studies have demonstrated interactions between S protein and innate immune system, including C-lectin type receptors (CLR), toll-like receptors (TLR) and neuropilin-1 (NRP1), and the non-immune receptor glucose regulated protein 78 (GRP78). Recognition of carbohydrate moieties clustered on the surface of the S protein may drive receptor-dependent internalization, accentuate severe immunopathological inflammation, and allow for systemic spread of infection, independent of ACE2. Furthermore, targeting TLRs, CLRs, and other receptors (Ezrin and dipeptidyl peptidase-4) that do not directly engage SARS-CoV-2 S protein, but may contribute to augmented anti-viral immunity and viral clearance, may represent therapeutic targets against COVID-19.

Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome

“…This suggests that the elevated CXCL9 and CXL10 in MIS-C are probably markers of increased IFN-g production in lymphoid organs and of secondary induction of pro-inflammatory cytokines and chemokines (e.g., IL-6, CXCL8, CCL2) by macrophages. In addition, the increase of these chemokines in patients with MIS-C might be partially related to the interaction of PAMPs and viral molecules with innate immune receptors, such as TLR3 (49,50).…”

Taste Dysfunction and Long COVID-19

“…The oral epithelial cells including the taste bud cells have been shown to express angiotensin-receptor-2 (ACE2), the entry receptor for viruses of the Coronaviridae family including the SARS-COV-2. Emerging evidence also suggest that the CoV-2 potentially uses multiple entry receptors such as the sialic acid receptors and the toll like receptors (TLR) for host cell entry (Vaira et al, 2020;Gadanec et al, 2021). Binding of SARS-CoV-2 to salivary sialic acid could interfere with the glycoproteins mediated transport of tastants and contribute to loss of taste (Milanetti et al, 2021).…”

Natural variants in SARS-CoV-2 Spike protein pinpoint structural and functional hotspots with implications for prophylaxis and therapeutic strategies

“…A cryo-electron microscopy study has already suggested that coronaviruses mask important immunogenic sites on their surface by glycosylation 46 . Furthermore, recent work suggests that changes in glycosylation sites on the S protein of the virus may affect recognition of the S protein by other potential human proteins and receptors, inducing the toll-like receptors, calcitonin-like receptors, and heat shock protein GRP78, thus leading to a more severe inflammation that characterizes a more severe form of COVID-19 47 .…”